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So My Brain Amyloid Level is “Elevated”—What Does That Mean?

Testing drugs to prevent or delay the onset of Alzheimer’s dementia and using them in the clinic will mean identifying and informing adults who have a higher risk of Alzheimer’s but are still cognitively normal. A new study from the Perelman School of Medicine at the University of Pennsylvania has shed light on how seniors cope with such information.

Center for Advanced Cellular Therapeutics to Rise on Penn Medicine Campus

The University of Pennsylvania recently reached an important milestone in its alliance with Novartis as it unveiled plans for the construction of a first-of-its-kind Center for Advanced Cellular Therapeutics (CACT) on the Penn Medicine campus in Philadelphia. The CACT will become the epicenter for research using Chimeric Antigen Receptor technology (CAR), which enables a patient’s T cells to be reprogrammed outside of the body so when they are re-infused into the patient, the T cells have the ability to “hunt” and destroy the cancer cells. Clinical trials using this approach have made headlines around the world.

Penn Medicine Names First Leader of Precision Medicine to Speed Delivery of Tailored Treatments to Patients

D. Gary Gilliland, MD, PhD, was recently named the inaugural Vice Dean and Vice President for Precision Medicine, a newly created role to position Penn Medicine as the nation’s top leader in the delivery of individualized medicine.

Comprehensive Parkinson’s Biomarker Test Has Prognostic and Diagnostic Value, Penn Medicine Team Reports

Perelman School of Medicine researchers at the University of Pennsylvania report the first biomarker results reported from the Parkinson’s Progression Markers Initiative (PPMI), showing that a comprehensive test of protein biomarkers in spinal fluid have prognostic and diagnostic value in early stages of Parkinson’s disease. The study is reported in JAMA Neurology.

Compared to healthy adults, the study found that people with early Parkinson’s had lower levels of amyloid beta, tau and alpha synuclein in their spinal fluid. In addition, those with lower concentrations of tau and alpha synuclein had greater motor dysfunction. And early Parkinson’s patients with low levels of amyloid beta and tau were more likely to be classified as having the postural instability-gait disturbance- dominant (PIGD) motor type of disease, where falling, freezing, and walking difficulty are common.

“Biomarkers for Parkinson’s disease such as these could help us diagnose patients earlier, and we’ve now shown that the simultaneous measurement of a variety of neurodegenerative disease proteins is valuable,” said study senior author Leslie M. Shaw, PhD, professor of Pathology and Laboratory Medicine at Penn Medicine. Dr. Shaw and John Q. Trojanowski, MD, PhD, director of the Penn Udall Center for Parkinson’s Research, are co-leaders of the Bioanalytics Core for the Parkinson’s Progression Markers Initiative, an international observational clinical study sponsored by The Michael J. Fox Foundation for Parkinson’s Research.

The team evaluated spinal fluid collected from baseline visits of the first 102 PPMI participants – 63 with early, untreated Parkinson’s disease and 39 healthy controls. The spinal fluid was evaluated for levels of five biomarkers: amyloid beta, total tau, phosphorylated tau, alpha synuclein and the ratio of total tau to amyloid beta. Spinal fluid measures of amyloid and tau are currently used in research to distinguish Alzheimer’s disease from other neurodegenerative diseases. In contrast to Alzheimer’s, where tau levels are higher than healthy controls, the study found that early Parkinson’s patients had lower levels of tau than healthy controls. One reason, researchers suggest, could be that interactions between tau and alpha synuclein may limit the release of tau into the cerebrospinal fluid of Parkinson’s patients.

“Through PPMI, we are hoping to identify subgroups of Parkinson’s patients whose disease is likely to progress at a different rate, as early as possible,” said Dr. Trojanowski. “Early prediction is critical, for both motor and dementia symptoms.”

The Parkinson’s PIGD motor subtype has been associated with a more rapid cognitive decline as well as greater functional disability. Using the biomarker test, this initial study found that levels of all spinal fluid biomarkers were lower in the PIGD motor subtype than other types of PD as well as healthy controls. In addition, amyloid beta and phosphorylated tau were at lower levels in the PIGD motor subtype, but were no different in tremor or indeterminate subtypes compared to normal controls.

This spinal fluid testing procedure is only being used in research studies, and will be continued to be evaluated and validated in a larger study of the PPMI cohorts.

In addition to leading the Bioanalytics Core of PPMI, Penn’s Parkinson’s Disease and Movement Disorders Center is one of the two dozen trial sites where volunteers are evaluated throughout the PPMI study. The Penn PDMDC has been part of the PPMI group studying people with early Parkinson’s disease as well as healthy adults since 2010, and began enrollment for a new, pre-symptomatic arm of the study in the summer of 2013. The pre-motor arm of PPMI is enrolling participants who do not have Parkinson’s disease and are living with one of three potential risk factors for PD: a reduced sense of smell (hyposmia); rapid eye movement sleep behavior disorder (RBD; a disorder in which the individual acts out his/her dreams); or a mutation in the LRRK2 gene (the single greatest genetic contributor to PD known to date).

“In addition to biomarker tests, validating risk factors could enable earlier detection of the disease and open new avenues in the quest for therapies that could slow or stop disease progression,” said PPMI trial site study leader Matthew Stern, MD, professor of Neurology and director of Penn’s Parkinson’s Disease and Movement Disorders Center.

Study: Association of Cerebrospinal Fluid β-Amyloid 1-42, T-tau, P-tau181, and α-Synuclein Levels With Clinical Features of Drug-Naive Patients With Early Parkinson Disease [JAMA Neurology]

Source: Penn Medicine

Penn Medicine’s New Center for Personalized Diagnostics Unlocks Cancer’s Secrets

Just like a massive iceberg jutting out of the ocean, many of cancer’s genetic underpinnings remain hidden under the surface, impossible to predict or map from above. The foreboding shadows and shapes that appear on CT scans and MRIs – and even in the field that doctors see when they zoom in to look at cancer cells under a high-powered microscope – are just the tip of the iceberg.

Penn Medicine’s new Center for Personalized Diagnostics, a joint initiative of the department of Pathology and Laboratory Medicine in the Perelman School of Medicine and the Abramson Cancer Center, is diving deeper into each patient’s tumor with next generation DNA sequencing. These specialized tests can refine patient diagnoses with greater precision than standard imaging tests and blood work, all with an aim to broaden treatment options and improve their efficacy.

“We’re using the most advanced diagnostic methods to unlock cancer’s secrets,” says David B. Roth, MD, PhD, chairman of the department of Pathology and Laboratory Medicine. “A tumor’s genomic profile is the most critical piece of information for an oncologist to have when they’re deciding what therapy to recommend. The results of tests in the Center for Personalized Diagnostics reveal a genetic blueprint of each patient’s tumor that is as discrete and singular as a fingerprint.”

The Center for Personalized Diagnostics unites top experts in genomic analysis, bioinformatics, and cancer genetics – who use the most sensitive data analysis tools available to identify the rarest of mutations – with oncologists who treat patients and design clinical trials to test new therapies. Together, their efforts will provide cancer patients with cutting-edge diagnostic and therapeutic options.

The first group of patients who are undergoing testing through the CPD includes those with blood cancers and solid tumors of the brain, melanoma, and lung. Throughout 2013, the tests will be expanded for a wider range of cancer patients. Results are available within two weeks – twice as fast as most commercially available testing panels. All new and relapsed Abramson Cancer Center patients will receive this testing – conducted via simple blood tests and/or biopsy of tumor tissue or bone marrow – as part of their evaluation and diagnostic process. Interpretation of results is communicated one-on-one to patients and their caregivers by physicians and genetic counselors.

In contrast to the CPD’s offerings, individual genetic tests – which now proliferate in the marketplace, even for healthy people who may be interested in going on a spelunking expedition through their DNA – are time consuming and expensive to conduct, and they often yield information which is not clinically actionable. When these tests are offered for cancer patients, patients are often left with only a veritable alphabet soup detailing genetic information, with few plans for how to use those findings to conquer their cancer.

Since the CPD began operating in early 2013, however, tests in 80 percent of patients revealed genetic mutations that may be used to alter their treatment course or clarify their prognosis. The results are playing a role in:

  • Matching patients with existing therapies designed to target mutations previously associated only with different cancers. For instance, some lung cancer patients exhibit mutations of the BRAF gene, which is targeted by drug Vemurafenib, initially developed and approved for melanoma. Testing in the Center for Personalized Diagnostics is helping clinicians make new connections that will expand the indications for existing drugs.
  • Helping physicians determine which treatments a patient will respond to, or how well they will tolerate a particular treatment. Patients with the blood cancer acute myelogenous leukemia who express a mutation known as DNMT3A, for instance, are known to respond to higher doses of the drug daunorubicin. Learning this type of information prior to beginning treatment can help oncologists select and dose drugs in a way that will reduce side effects and boost patients’ quality of life during treatment – and increase their chance of completing their prescribed regimen.
  • Identifying patients who are likely to have a poor prognosis if treated with first-line therapies, which allows clinicians to set up a cascade of alternative therapies or, in the case of some blood cancer patients, expedite the search for a matching bone marrow donor.
  • Detecting resistance mutations that could slow or halt patients’ response to targeted drugs, which allows for custom-designed combination therapies to attack tumors through multiple pathways.

The Center’s research agenda operates in parallel with its clinical care mission. Each patient’s test results will add to an enormous repository of genomic mutation profiles that, combined with the ability to follow patients over time, will help clinical researchers identify new markers and mutation profiles to better predict the course of an individual patient’s treatment response and suggest new targets for therapy. As new mutations are detected and novel treatment options are identified, the gene testing panels will be modified and expanded, creating an evolving, real-time mutation profiling option.

“We see 11,500 newly diagnosed patients each year in the Abramson Cancer, and hundreds of others who seek our help when their cancers have not responded, or have returned, after receiving standard therapies elsewhere,” said Chi Van Dang, MD, PhD, director of the Abramson Cancer Center. “A key part of our mission is to provide each of these patients these tests as soon as possible, so that we can quickly tailor a treatment regimen that provides them the greatest chance of a cure.”

Source: Penn Medicine